The vast majority of diseases that cause catastrophic loss of vision do so as a result of abnormal angiogenesis and associated retinal edema, hemorrhage and gliosis. The research program supported by this grant for the past 15 years initially focused on understanding the role of adhesion receptors (e.g., integrins) in ocular angiogenesis and developing ways to inhibit abnormal neovascularization. Several years ago, we indentified and characterized endothelial and myeloid progenitor cells as potential therapeutics useful for vascular- and neurotrophic rescue in the treatment of retinal vascular and neuronal degenerative diseases. By studying the fates of these progenitor cells after implantation into eyes of rodent models of retinal disease, we indentified additional cell populations (e.g., microglia, astrocytes, Muller glia) critical to maintaining normal vascular and neuronal networks in the retina. In the next project period, we will continue our studies on mechanisms of basic retinal angiogenesis, developing approaches to inhibit abnormal vessel growth and understanding paracrine effects of endothelium and glia on neuronal parenchyma. We will use novel Cre-inducible transgenic mice in which we have deleted selected angiogenesis-associated genes in specific cell types. The development of the retinal, as well as regression of the hyaloidal, vasculature will be studied in these mice under normal and hypoxic conditions. We will also assess the effect of injected and novel cell-based delivery systems for the delivery of combination angiostatic and neurotrophic therapies in models of retinal neovascularization. The overarching hypothesis driving this research program is that physiological angiogenesis differs from pathological angiogenesis largely as a result of miscues between interacting cell populations and their micro-environments; while the principle participant is the endothelial cell, other cells are critical to vessel formation and these include microglia, inflammatory cells and even neurons. We will continue to explore the relationship between these cells types, how they influence the extracellular matrix (e.g., microenvironment) and what molecules they influence during cross-talk. This will be accomplished through the following Specific Aims: (1) We will explore the potential utility of combination angiostatic therapy and targeted cell-based delivery of angiostatics and neurotrophics in treating ocular neovascularization; (2) We will explore and define the role of non-endothelial cells in retinal angiogenesis and vascular regression; and (3) Using novel metabolomic analyses we will identify molecules associated with hypoxia driven angiogenesis in physiologically relevant models of angiogenesis.